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Marlene Garcia Swider is a regulatory project manager in the division of gastroenterology products at CDER, FDA
Outsourcing introduces considerable complexity into ensuring compliance with good manufacturing practices. This article offers FDA guidance for how to ensure compliance in the outsourcing environment.
Many drug manufacturers may not have the capability to perform all manufacturing operations at their own establishments for economic reasons. Others opt for subcontracting their operations. Outsourcing introduces considerable complexity into ensuring compliance with good manufacturing practices. This article offers FDA guidance for how to ensure compliance in the outsourcing environment.
Historically, the manufacture of biological products in the United States involved a limited number of firms that were responsible for all the steps in the process including drug development, testing, labeling, packaging, and distribution to the markets. Since then, an increase in the demand for new products, along with market pressure for innovation, has fostered the growth of specialized firms and subsequent outsourcing.
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According to CDER's guidance for industry, Quality Systems Approach to Pharmaceutical CGMP Regulations, outsourcing involves hiring a second party under a contract to perform the operational processes that are part of a manufacturer's inherent responsibilities.1 For biological products, outsourcing refers to the delegation of manufacturing responsibilities to different types of cooperative arrangements—from the license applicant to a contractor. These arrangements share a common economic goal—bringing products to market more quickly at reduced costs. The FDA's guidance to industry, Cooperative Manufacturing Arrangements for Licensed Biologics, describes different types of manufacturing arrangements for outsourcing.2 Cooperative arrangements recognized by the FDA include: a) a license holder obtaining a short supply product from other than the licensed facilities (see 21 CFR 601.22 for more details); b) two or more licensed firms sharing manufacturing through each firm's individual responsibility for specific aspects of the manufacture of a product with neither being licensed for all aspects of the manufacture; and c) firms performing all or some of the product manufacture as a service to the license holder. Regardless of the type of cooperative manufacturing arrangement, all firms involved in the outsourcing of a manufacturing process must be in compliance with the FDA regulations.
According to the FDA's regulations, the manufacturer is legally responsible for the manufacture of a biological product. Both license holders and contractors fall under this definition because they take part in the manufacture of the biological product. License holders and contractors have responsibilities under the law (see the PHS Act, 21 CFR Parts 210, 211, 600 through 680, and 820 for more details).
The license holder ensures compliance with product and establishment standards through the implementation of current good manufacturing practices (cGMPs). The contractor maintains effective and timely communication with the license holder. Contractors must inform license holders of all deviations in manufacturing methods, adverse events, tests and investigations possibly affecting the product, proposed changes in manufacturing, and any changes in the facilities.
Without exception, all outsourcing participants must comply with FDA regulations. Failure to comply with cGMPs or to fulfill license requirements may justify compliance action. Details for complying with cGMPS can be found in the Food, Drug, and Cosmetic Act (21 USC 301) and the CFR.
Outsourcing introduces considerable complexity into ensuring compliance with cGMPs. Outsourcing can result in having multiple contractors involved in the manufacture of a single compound. Today, it is not uncommon for a biological product manufacturing process to include more than 10 participant sites. This increase in participants translates into a commensurate increase in FDA inspections.
Inspections have been expanding to include ex-US firms as manufacturers seek to reduce costs. This has resulted in an explosion of travel time and expenses for inspection. Foreign manufacturing site inspections necessitate obtaining country-specific clearances, multilingual staff to manage and control documentation, and increased interaction by the FDA inspection staff with a variety of international business cultures.
In their interactions with foreign manufacturing sites, the FDA inspectors encounter different local regulatory requirements and compliance expectations. These interactions also may entail translations of standard operating procedures (SOPs) into multiple languages. The need to conduct foreign inspections of manufacturing sites has led to an increased dependence on information technology and reliance on electronic meetings with new communication modalities for more effective communication.
Furthermore, interactions with more firms also translate into more reviews and inspections of manufacturing support sites. These sites include laboratories, suppliers, labelers, storage sites, and packagers in and outside the US. Warehouses for unlabeled products also may be inspected. (Warehouses for finished labeled and packaged material usually are not inspected unless problems with the storage conditions exist.)
The complexities faced by the FDA translate into complications for the manufacturing firms. Each addition of a contract manufacturer means another supplement to an existing biological license application. Additional inspections may be needed for these submissions, depending on the manufacturing process or testing being contracted. For example, a contracted bulk manufacturer or a filling manufacturer normally requires a prior approval supplement and a release testing laboratory generally requires a change-to-be-effected in 30 days supplement.
The FDA encourages manufacturers to submit thorough and comprehensive submissions. To expedite the process, drug manufacturers must follow the FDA regulations and guidelines as closely as possible. These guidelines are the basis for reviewing submissions and are the documents most familiar to the FDA reviewers. Editing and organizing the material presented to the FDA in a coherent document can pay huge dividends for the applicant. Effective communication facilitates understanding of the material presented and saves review time. Using a table of contents and a list of acronyms minimizes misunderstandings. Furthermore, providing background information with each submission clarifies the product's history and the company's future plans. Poor submissions, like poor manufacturing compliance history, can slow the review and approval process of submissions.
Regular and timely communication with the regulatory project managers
The FDA encourages communication with the agency. Different avenues are available to manufacturing firms to accomplish this. For example, alerting the regulatory project manager (RPM) responsible for a submission of any correspondence and amendments being sent to the agency can be very useful both to the firm and to the FDA. This builds trust and enables both parties—the RPM and applicant—to keep abreast of progress with each submission.
Meet with the agency
The FDA encourages meetings because carefully planned and well-run meetings facilitate understanding of the material being presented to the agency. Teleconferencing is an option when a face-to-face meeting is not possible. Meetings facilitate a mutual understanding of each party's needs.
Understand regulations and guidelines
Taking the time to understand how new regulations can affect manufacturing operations, and asking the FDA questions as needed can help the company. Also, gaining an understanding of the regulations and guidelines can save time, money, and resources.
Visit the FDA web site and keep informed
The agency believes in clear and timely communication. The FDA's web site is therefore constantly updated with the most current information available to the public. There are options to e-mail questions and to provide comments on regulatory policies.
Single-source editing of the submission
One of the most common mistakes made by firms is not having their submission edited by a single source. Reviewers often read submissions containing sections written by different authors that do not agree among themselves. The sections sometimes are incomplete or even contradictory. This is not only confusing for the FDA reviewers, but also wastes precious review time. Such a lack of commitment in creating a quality submission could raise questions about the company's commitment to quality in general.
Limit information to what is being requested
Manufacturing firms should be aware that providing more information than what is requested maybe unnecessary. More information takes more review time and does not necessarily improve the quality of the information in the submission.
Learn from others' successes and failures
Firms need to be proactive and informed. The agency's web site gives access to current problems confronted by the FDA. News about FDA actions is also available through various media outlets including professional journals. Firms must learn from examining how the agency confronts emerging issues.
Help the FDA help you
Be sure to provide complete information about your facilities, including but not limited to the FDA establishment identifier number, correct street address of the actual manufacturing plant, the name and number of a contact person at each plant, and the exact function of the facility in the context of the drug application. All facilities should be submitted in one section of the application, so that they are easy to locate for the reviewer. Also, a quick response to the agency's queries can reduce guessing time spent on a submission and earn quick feedback from the FDA.
Cooperation is also key. Good team players help each other accomplish their goals by respectfully listening to each other's point of view and without taking antagonistic positions. Working together accelerates review and ensures approvals of qualified products on time.
Put it in writing
Finally, the FDA recommends having written agreements with contractors that identify: 1) the locations to be used for manufacture; 2) the responsibilities of each participant; 3) the specific product shipped to the contract facility; 4) the manner and conditions of shipment; 5) product segregation SOPs; 6) a commitment to inform the license holder of errors and deviations; and 7) how and when the contract facility will be audited. Regulatory actions with legal consequences can be easily avoided with a well-written agreement.
One of the FDA's goals is to facilitate product development and manufacturing flexibility, and therefore, it supports advancement of new and innovative ways that will lower the cost of drug development while advancing the critical path for a drug product's review. Providing guidance to manufacturing firms on different types of outsourcing and recommending how to improve their submissions is one more way the FDA shows support for this goal.
This article was written by Marlene Garcia Swider in her private capacity. No official support or endorsement by the Food and Drug Administration is intended or should be inferred.
Marlene Garcia Swider, MHSA, is a regulatory project manager in the division of gastroenterology products at CDER, FDA, Silver Spring, MD, 301.796.2104, firstname.lastname@example.org
1. US Food and Drug Administration. Guidance for Industry. Quality systems approach to pharmaceutical CGMP regulations. Rockville, MD; 2006 Sept. Available from: www.fda.gov/cder/guidance/7260fnl.htm.
2. US Food and Drug Administration. Guidance for Industry. Cooperative manufacturing arrangements for licensed biologics/ Rockville, MD; 2008 Nov. Available from: www.fda.gov/cber/gdlns/coopmfr.htm.